Pediatric HIV-1 infection is a significant source of childhood morbidity and mortality worldwide. Improved understanding of the virus-host dynamic in early infection is important for the development of effective strategies to prevent or treat HIV-1 infection. Over the past funding period, work supported by this grant has made several contributions to our understanding of the relationship between cell-mediated immune responses and viral load in early pediatric HIV-1 infection. Work outlined in this renewal application will continue our studies characterizing the generation, specificity, and function of HIV-1 specific CD4+ and CD8+ T cell responses in young infants and their relationship to HIV-1 replication. Collectively, these projects address the hypotheses that the role of HIV-1 specific CD8+ T cells in the pathogenesis of vertical HIV-1 infection is dependent not only on the timing of detection, magnitude, and breadth of CD8+ T cell responses but also on the founder viral sequence, the availability of CD4+ T cell help, and on CD8+ T cell specificity and functional properties. The following specific aims will be examined: 1) To sequentially examine the timing of detection, magnitude, specificity, and functional properties of HIV-1-specific CD8+ T lymphocyte responses in young, HIV-1 infected infants; 2) To evaluate maternal and early infant sequences for CD8+ T cell escape variants and for evidence of CD8+ T cell selective pressure in vivo; 3) To conduct Phase I clinical trials that examine the safety and immunogenicity of multivalent pox-based vaccines in children with long-term control of viral replication following early, potent combination ART. Data from these studies will improve our understanding of the pathogenesis of early pediatric HIV infection and contribute to the development of strategies to prevent or modify pediatric HIV-1 infection.